The new antiviral drug, adefovir dipivoxil (hereinafter “AD”), is a nucleotide reverse transcriptase inhibitor with the nomenclature of 9-[2-[bis(pivaloyloxy)-methoxy]phosphinyl]methoxy)ethyl]adenine, which exhibits a marked invivo antiviral activity against both HIV and HBV. For more information about its antiviral activities, see Barditch-Crovo P et al, J Infect Dis, 176(2): 406, 1997, and Starrett et al, J Med Chem, 37:1857-1864, 1994.
Studies show that the AD in nature exists in two forms: amorphous and crystal. PCT patent application “pharmaceutical formulations” (International Publication NO. W00035460A) discloses a more stable AD pharmaceutical formulations comprising anhydrous crystalline AD and dihydrate crystalline AD and an alkaline excipient. Another application, W09904774A, discloses compositions containing one or more crystalline AD, wherein the AD comprises the following crystalline forms with different melting points: the anhydrous crystalline form, the hydrated form, the solvate form, and the salt crystalline form.
It is well known that different crystalline forms of a drug compound have different melting points, solubility, and density of said drug compound. At the same time, the fluidity and flexibility of crystals of said compound and the dissolution rate, stability, and effectiveness of said crystals in a pharmaceutical formulation may differ from one to another. For example, although the γ-type of indolacin is less stable, it has better performance in solubility, bioavailability and pharmacology than that of the α and β type. In addition, different crystalline forms may be enantiotropic under certain conditions. For instance, during the process of wet granulation, the drug may be dissolved in a solvent added and recrystallized in the later drying step to obtain a new crystalline form, which may affect the dissolution of the drug and the uniformity of the pharmaceutical formulation containing this drug. Therefore it is necessary to select a crystalline form with a suitable stability during manufacture and storage. Taking insulin zinc as an example, the dissolution rate of its stable form is slower than that of its metastable one. Thus a suspension of short, medium or long term release may be obtained by adjusting the proportion of these two crystalline forms. Therefore, it is not always necessary to adopt the most stable crystalline form in pharmaceutical industry, which depends on a lot of factors, such as the clinical uses, producing costs and cycles, as well as techniques and so on.